Acyl desaturase enzymes catalyze the formation of double bonds in fatty acids derived from either dietary sources or de novo synthesis in the liver. Mammals synthesize at least three fatty acid desaturases of differing chain length specificity that catalyze the addition of double bonds at the Δ9, Δ6, and Δ5 positions. Stearoyl-CoA desaturases (SCDs) introduce a double bond in the Δ9-position of saturated fatty acids. The preferred substrates are palmitoyl-CoA (16:0) and stearoyl-CoA (18:0), which are converted to palmitoleoyl-CoA (16:1) and oleoyl-CoA (18:1), respectively. The resulting mono-unsaturated fatty acids are substrates for incorporation into phospholipids, triglycerides, and cholesteryl esters.
A number of mammalian SCD genes have been cloned. For example, two genes have been cloned from rat (SCD1, SCD2) and four SCD genes have been isolated from mouse (SCD1, 2, 3, and 4). A single SCD gene, SCD1, has been characterized in humans. A second human SCD isoform has recently been identified, and because it bears little sequence homology to alternate mouse or rat isoforms it has been named human SCD5 or hSCD5. (See WO 02/26944 of Brownlie).
While the basic biochemical role of SCD has been known in rats and mice since the 1970's (Jeffcoat R. and James, A T. Elsevier Science, 4: 85-112 (1984); de Antueno, R J. Lipids 28(4)285-290 (1993)), it has only recently been directly implicated in human disease processes. Thus, an SCD1 enzyme highly useful in such studies has been identified and is further described in Brownlie et al, WO 01/62954 (30 Aug. 2001), the disclosure of which is hereby incorporated by reference in its entirety.
A number of mechanisms for the inhibition or modulation of SCD activity are available to suggest a means of approaching the rational design of SCD-modulating agents. Among these are the following, each of which serves to identify a specific mechanistic class of compound. One class of compounds includes those inhibitors that effectively inhibit SCD1 expression. This are believed to include putative PPAR agonists, such as thiazolidinedione compounds, and certain polyunsaturated fatty acids. A leading thiazolidinedione, troglitazone, has recently been withdrawn from human clinical use having been found to have an undesirable toxicity profile.
A second class of SCD inhibitors includes those inhibitors that effectively inhibit SCD1 enzymatic activity directly. Known examples include thia-fatty acids, cyclopropenoid fatty acids, and certain conjugated linoleic acid isomers. Specifically, Cis-12, trans-10 conjugated linoleic acid is known to effectively inhibit SCD enzyme activity and reduce the abundance of SCD1 mRNA while Cis-9, trans-11 conjugated linoleic acid does not. Cyclopropenoid fatty acids, such as those found in stercula and cotton seeds, are also known to inhibit SCD activity. For example, sterculic acid (8-(2-octyl-cyclopropenyl)octanoic acid) and Malvalic acid (7-(2-octyl-cyclopropenyl)heptanoic acid) are C18 and C16 derivatives of sterculoyl- and malvaloyl fatty acids, respectively, having cyclopropene rings at their Δ9 position. These agents inhibit SCD activity by inhibiting Δ9 desaturation. Other agents include thia-fatty acids, such as 9-thiastearic acid (also called 8-nonylthiooctanoic acid) and other fatty acids with a sulfoxy moiety.
Finally, the third class of inhibitors includes those agents that are capable of interfering with the proteins essential to the desaturase system, such as those agents that interfere with cytochrome b5, NADH (P)-cytochrome b5 reductase, and terminal cyanide-sensitive desaturase. This latter group of compounds may well be toxic and therefore of little use.
The known modulators of delta-9 desaturase activity are either not useful for treating the diseases and disorders linked to SCD1 biological activity as claimed in this invention, or else they are otherwise unsatisfactory therapeutic agents. The thia-fatty acids, conjugated linoleic acids and cyclopropene fatty acids (malvalic acid and sterculic acid) are neither useful at reasonable physiological doses, nor are they specific inhibitors of SCD1 biological activity, rather they demonstrate cross inhibition of other desaturases, in particular the delta-5 and delta-6 desaturases by the cyclopropene fatty acids. In some cases, it is preferred to identify compounds which inhibit SCD specifically and do not cross inhibit delta-5 desaturase and/or delta-6 desaturase.
Using such methodology, new classes of compounds have been identified and disclosed herein that are useful in modulating SCD activity and thereby regulating lipid levels, especially plasma lipid levels.